Remimazolam-Based Anesthesia in Patients with Heart Failure Due to Mitral Regurgitation and Low Left Ventricular Function: A Case Series.

Background and Objectives: Remimazolam is a new ultrashort-acting benzodiazepine anesthetic. Remimazolam appears to be useful in patients with severe valvular disease because of its minimal cardiovascular impact. In this retrospective case series study, we assessed the efficacy and safety of remimazolam for maintaining hemodynamic stability during anesthetic induction and maintenance. Cases: MitraClip was performed on 18 cases with severe mitral regurgitation with low left ventricular function who presented with heart failure, and remimazolam was administered for general anesthesia with induction (12 mg/kg/h) and maintenance (1 mg/kg/h). The impact of remimazolam on the hemodynamics at anesthetic induction and during anesthetic maintenance was investigated retrospectively using electronic medical records. Blood pressure decreased significantly during anesthetic induction with remimazolam (78.5 [72, 81.25] and 66.1 [62.2, 74.2], median [IQR], p = 0.0001), but only mildly, by about 10 mmHg. There was no significant change in the cardiac index (2.0 [1.8, 2.4] vs. 1.9 [1.8, 2.3], p = 0.57642) or pulse rate (73.5 ± 8.85 vs. 74.7 ± 11.7, mean ± SD, p = 0.0876) during anesthetic induction with remimazolam. All patients underwent MitraClip without major hemodynamic concerns, with no or small increases in inotropes. Conclusions: Remimazolam may be used safely in patients with severe mitral regurgitation and low left ventricular function presenting with heart failure.

A retrospective comparative study of anesthesia with remimazolam and remifentanil versus dexmedetomidine and remifentanil for transcatheter aortic valve replacement.

Remimazolam, an ultrashort-acting benzodiazepine, allows for rapid and reliable arousal. Rapid awakening using remimazolam may be beneficial in transcatheter aortic valve replacement (TAVR), as it allows rapid detection of neurologic deficits. The purpose of this study was to compare arousal time and outcomes between monitored anesthesia care (MAC) with remimazolam and remifentanil and conventional MAC with dexmedetomidine, propofol, and remifentanil. This study was a single center retrospective study. All TAVR cases performed under MAC (MAC-TAVR) at our institution between 2019 and 2021 were included. Patients were classified by anesthesia method into remimazolam and dexmedetomidine groups. Among 258 MAC-TAVR patients, 253 were enrolled. After propensity score matching, 76 patients were assigned to each group. The time from end of drug-administration to arousal [20.0 (16.0, 24.0) min vs. 38.5 (30.0, 56.3) min, p < 0.0001] and the time from attempted-arousal to arousal [1.0 (1.0, 1.0) min vs. 12.5 (3.0, 26.8) min, p < 0.0001] were significantly shorter in the remimazolam group. There was no significant difference in the length of ICU stay [2.0 (2.0, 2.0) days vs. 2.0 (2.0, 2.0) days, p = 0.157] and postoperative hospital stay [6.0 (4.0, 9.0) days vs. 5.0 (4.0, 8.0) days, p = 0.262].Trial registration: Clinical trial number: R03-123, Registry URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000051635 Registration number: UMIN000045195, Principal investigator's name: Atsuhiro Kitaura, Date of registration: 20 August 2021.

Successful Nafamostat Mesilate Administration for Andexanet Alfa-Induced Heparin Resistance.

Andexanet alfa is an analog of activated factor X and is used as an antagonist of anti-activated factor X agents. Andexanet alfa is useful for hemostasis in emergent bleeding during direct oral anticoagulant administration, which contributes to safety. In patients undergoing surgery with cardiopulmonary bypass because of heparin resistance, anesthesiologists are faced with a choice of anticoagulants. Herein, we experienced anesthesia for vascular prostheses with cardiopulmonary bypass for acute aortic dissection in a patient who had received andexanet alfa preoperatively. Heparin was initially used as the anticoagulant during cardiopulmonary bypass; however, despite the administration of large doses and antithrombin III preparations, anticoagulation was insufficient. Therefore, nafamostat mesilate was administered and sufficient anticoagulation was attained. The patient completed surgery under cardiopulmonary bypass, coagulation function was recovered shortly after withdrawal, and no obvious adverse effects were observed.

Two Cases of Inadequate Response to Remimazolam.

We report the inadequate efficacy of remimazolam in two patients undergoing long-term benzodiazepine analog therapy. Remimazolam is a recently developed ultrashort-acting benzodiazepine. It is primarily used as an anesthetic in surgical procedures, as it has minimal effect on cardiac function and antagonists are available. It is expected to become more widely used in the future. On the other hand, similar to other benzodiazepines, benzodiazepine tolerance can also pose a challenge with remimazolam. Herein, we report two cases who were taking long-term oral benzodiazepine analogs. One patient did not fall asleep despite a sufficient dose of remimazolam and required a change to propofol. The other patient required a high dose of remimazolam to fall asleep; however, multiple signs of arousal were noted intraoperatively. Our findings suggest that remimazolam may not be an ideal anesthetic in long-term benzodiazepine analog users. Comprehensive assessment of preoperative medications and careful monitoring of intraoperative sedation levels are necessary. Furthermore, it may be advisable to consider the use of alternative agents such as propofol.

Nine-Second Cardiac Arrest in a Patient With Anti-mitochondrial Antibody-Positive Myopathy Under General Anesthesia.

A small percentage of cases of dermatomyositis are positive for anti-mitochondrial antibodies (AMA), a known marker for primary biliary cirrhosis. AMA-positive myositis is a rare disease that has been reported to be accompanied by myocarditis, resulting in low left ventricular function, supraventricular arrhythmias, and abnormalities of the conduction system. We present a case of AMA-positive myocarditis resulting in sinus arrest during general anesthesia. A 66-year-old female with AMA-positive myocarditis underwent artificial femoral head replacement for osteonecrosis of the femoral head under general anesthesia. During general anesthesia, a nine-second sinus arrest occurred without any inducement. The sinus arrest was thought to be influenced by not only over-suppression caused by severe supraventricular tachycardia derived from sick sinus syndrome but sympathetic depression caused by general anesthesia. Because of the potential for life-threatening cardiovascular events during anesthesia in patients with AMA-positive myositis, it was considered essential to provide adequate preoperative management and intraoperative monitoring during anesthesia for patients with this disease. Herein, we report our case with a literature review.

Dynamic sequential extraction procedure using a four-channel circulating flow system for extracting Hg from soil samples.

Mercury (Hg) is harmful to the human body. Its physical properties and toxicity differ greatly depending on its chemical form. The quantification of soluble Hg in soils or sediments is crucial for preventing further environmental contamination by Hg sources such as products, processes, and storage. In this study, the risk of leachable Hg that release from soil to the hydrosphere was evaluated by the sequential extraction procedure (SEP), a speciation method of a targeted element based on the solubility of its various compounds. The SEP, which consists of a four-channel circulating flow system (FCFS), was developed to reduce the time and amount of liquid required for SEP of leachable Hg in the Bloom method, which is a conventional SEP for Hg in a solid sample. The SEP with FCFS was optimized by considering the impact of extractant volume, circulation extraction time, and flushing of the extraction line. In the three-step (Fraction 1-3) sequential extraction of leachable Hg in soil samples, the optimized SEP with FCFS required 45 mL of extractant and 2.5 h, while the common batch SEP required 75 mL of extractant and 49 h. Furthermore, the combination of the SEP with FCFS for the leachable forms (Fraction 1-3) and the batch method for the insoluble forms (Fraction 4-5) was applied to the five-step SEP of Hg from CRM-JSAC0403. The sum of Hg concentrations that were classified into five fractions was in good agreement with that obtained from the batch method for all extraction, indicating that there are no significant differences in the concentrations extracted from the four channels.

Simple mercury determination using an enclosed quartz cell with cold vapour-atomic absorption spectrometry.

A simple method for determining total inorganic mercury (Hg) in solution using an enclosed quartz cell applying cold vapour-atomic absorption spectrometry (CV-AAS) can reduce sample volume, reductant, and cost compared with those of official methods. The Hg determination under the optimised conditions achieves precision similar to that of conventional CV-AAS.

Advanced glycation end-products reduce lipopolysaccharide uptake by macrophages.

Hyperglycaemia provides a suitable environment for infections and the mechanisms of glucose toxicity include the formation of advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups. Among AGE-associated phenotypes, glycolaldehyde-derived toxic AGE (AGE-3) is involved in the pathogenesis of diabetic complications. Internalisation of endotoxin by various cell types contributes to innate immune responses against bacterial infection. An endotoxin derived from Gram-negative bacteria, lipopolysaccharide (LPS), was reported to enhance its own uptake by RAW264.7 mouse macrophage-like cells, and an LPS binding protein, CD14, was involved in the LPS uptake. The LPS uptake induced the activation of RAW264.7 leading to the production of chemokine CXC motif ligand (CXCL) 10, which promotes T helper cell type 1 responses. Previously, we reported that AGE-3 was internalised into RAW264.7 cells through scavenger receptor-1 Class A. We hypothesized that AGEs uptake interrupt LPS uptake and impair innate immune response to LPS in RAW264.7 cells. In the present study, we found that AGE-3 attenuated CD14 expression, LPS uptake, and CXCL10 production, which was concentration-dependent, whereas LPS did not affect AGE uptake. AGEs were reported to stimulate the receptor for AGEs and Toll-like receptor 4, which cause inflammatory reactions. We found that inhibitors for RAGE, but not Toll-like receptor 4, restored the AGE-induced suppression of CD14 expression, LPS uptake, and CXCL10 production. These results indicate that the receptor for the AGE-initiated pathway partially impairs the immune response in diabetes patients.

Propofol suppresses the His-ventricular conduction in paediatric patients.

WHAT IS KNOWN AND OBJECTIVE: Propofol is the most commonly used intravenous anaesthetic worldwide and is considered to be safe for all ages. However, there have been some reports that propofol induces severe atrioventricular (AV) blocks in humans and some studies demonstrated that propofol suppressed the cardiac conduction system in animals. A precise mechanism by which the block is induced has not been elucidated yet in humans. The objective of this study was to investigate the effects of propofol on the cardiac conduction system and the cardiac autonomic nervous balance in children. METHODS: We enrolled 23 paediatric patients (age: 6-15 years; males: 16, females: 7) who were scheduled to undergo radiofrequency catheter ablation (RFCA) under general anaesthesia. Anaesthesia was induced with 2 mg/kg propofol and 0.5 µg/kg/min remifentanil, and tracheal intubation was performed with the aid of 1 mg/kg rocuronium. Anaesthesia was maintained with 5-7 mg/kg/h propofol and 0.2 µg/kg/min remifentanil during the RFCA. After the completion of the RFCA, anaesthesia was further maintained with 5 mg/kg/h propofol and 0.2 µg/kg/min remifentanil for at least 10 min (LC: low propofol concentration state), followed by the injection of 2 mg/kg propofol and the infusion of 10 mg/kg/h propofol for 10 min (HC: high propofol concentration state). The sinus node recovery time (SNRT), sinoatrial conduction time (SACT), atrial-His (AH) interval and the His-ventricular (HV) interval were measured at the end of both the LC and HC. Cardiac autonomic regulation was simultaneously assessed based on heart rate variability. RESULTS AND DISCUSSION: Propofol significantly suppressed intrinsic cardiac HV conduction, but did not affect the SNRT, SACT or the AH interval. As HV blocks, which occur below the His bundle, are often life-threatening, the HV conduction delay may be a cause of severe AV blocks induced by propofol. Propofol directly suppressed parasympathetic nerve activity, and sympathetic nerve activity was also suppressed. WHAT IS NEW AND CONCLUSION: These results indicate that propofol suppresses the HV conduction and might help to elucidate the mechanism by which propofol causes lethal AV blocks.

Effects of scavenger receptors-1 class A stimulation on macrophage morphology and highly modified advanced glycation end product-protein phagocytosis.

Advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups, play an important role in several diseases and aging processes including angiopathy, renal failure, diabetic complications, and neurodegenerative diseases. Among AGE-associated phenotypes, toxic AGEs, glyceraldehyde-derived AGE-2, and glycolaldehyde-derived AGE-3 are involved in the pathogenesis of diabetic complications. In addition, macrophages are reported to remove extracellular AGEs from tissues via scavenger receptors, leading to the progression of atherosclerosis. In the present study, we found that AGE-2 and AGE-3 enhanced their own endocytic uptake by RAW264.7 mouse macrophage-like cells in a concentration-dependent manner. Furthermore, we demonstrated, for the first time, the morphology of phagocytic macrophages and the endocytosis of AGE particles. The toxic AGEs induced the expression of a scavenger receptor, CD204/scavenger receptors-1 class A (SR-A). Notably, an antibody against CD204 significantly prevented toxic AGE uptake. Moreover, an SR-A antagonistic ligand, fucoidan, also attenuated the AGE-2- and AGE-3-evoked uptake in a concentration-dependent manner. These results indicated that SR-A stimulation, at least in part, plays a role in AGE uptake.

Interleukin-18 Amplifies Macrophage Polarization and Morphological Alteration, Leading to Excessive Angiogenesis.

M2 macrophage (Mφ) promotes pathologic angiogenesis through a release of pro-angiogenic mediators or the direct cell-cell interaction with endothelium in the micromilieu of several chronic inflammatory diseases, including rheumatoid arthritis and cancer, where interleukin (IL)-18 also contributes to excessive angiogenesis. However, the detailed mechanism remains unclear. The aim of this study is to investigate the mechanism by which M2 Mφs in the micromilieu containing IL-18 induce excessive angiogenesis in the in vitro experimental model using mouse Mφ-like cell line, RAW264.7 cells, and mouse endothelial cell line, b.End5 cells. We discovered that IL-18 acts synergistically with IL-10 to amplify the production of Mφ-derived mediators like osteopontin (OPN) and thrombin, yielding thrombin-cleaved form of OPN generation, which acts through integrins α4/α9, thereby augmenting M2 polarization of Mφ with characteristics of increasing surface CD163 expression in association with morphological alteration. Furthermore, the results of visualizing temporal behavior and morphological alteration of Mφs during angiogenesis demonstrated that M2-like Mφs induced excessive angiogenesis through the direct cell-cell interaction with endothelial cells, possibly mediated by CD163.

A spinal cord infarction that occurred after laparoscopic gastrectomy performed under general anesthesia and epidural analgesia.

BACKGROUND: Spinal cord infarction (SCI) after epidural anesthesia is quite rare. Although most cases of perioperative SCI are associated with aortic, cardiac, or spinal surgery, and/or abnormal preoperative conditions, such as spinal stenosis or hypercoagulopathy, intraoperative events, such as severe hypotension or epidural puncture and catheterization, can be contributory factors. CASE PRESENTATION: A 52-year-old male was underwent laparoscopic gastrectomy. Before induction of general anesthesia, an epidural catheter was placed without any problems. The patient had no pain and no complaint just after the operation, but suddenly complained of back pain and anuria, and could not move either of his lower limbs 30 h after the operation. As we thought that the incident would be caused by the migration of the epidural catheter into the subarachnoid space, we removed the catheter, but there was no recovery of the symptoms even 20 h later. The magnetic resonance imaging (MRI) scan showed no hematoma in the epidural space but an abnormal signal within the spinal cord, extending from the Th3 to Th8 levels, which was consistent with the SCI. Unfortunately, the patient's recovery from the paraplegia and abnormal sensation was poor. CONCLUSIONS: When a patient complains of lower limb muscle weakness and/or abnormal sensations, it is important to perform an MRI examination and treatment as early as possible to avoid permanent paraplegia, especially after epidural puncture and catheterization.

Sevoflurane causes greater QTc interval prolongation in chronically hyperglycemic patients than in normoglycemic patients.

QTc interval prolongation is a serious diabetic complication and increases mortality rate. Hyperglycemia inhibits the rapid component of delayed rectifier potassium channel currents (Ikr) and prolongs the QTc interval on electrocardiograms. Sevoflurane also inhibits the Ikr and causes QTc interval prolongation. In fact, torsade de pointes occurred in a patient with poorly controlled diabetes mellitus during sevoflurane anesthesia. We enrolled 74 patients, including 37 normoglycemic patients (glycated hemoglobin [HbA1c]: <6.5%) (NG group) and 37 chronically hyperglycemic patients (HbA1c: ≥6.5%) (HG group). Anesthesia was induced with 2 mg/kg propofol and 0.3 µg/kg/min remifentanil, and maintained with 2% sevoflurane in 40% O2 and 0.2-0.3 µg/kg/min remifentanil. The QT interval and Tp-e interval (from the peak to the end of the T wave) were measured before and at 5, 10, 30, 60, 90, and 120 min after the administration of sevoflurane and adjusted for the patient's heart rate (QTc and Tp-ec, respectively). P-values of <0.05 were considered statistically significant. The QTc and the Tp-ec intervals of the two groups did not differ significantly before the administration of sevoflurane. The QTc interval gradually increased with time in both groups and was significantly longer than the baseline value at 10 min after the administration of sevoflurane in both groups. The QTc interval of the HG group was significantly longer than that of the NG group at 90 min and 120 min after the administration of sevoflurane. The Tp-ec interval was not affected by sevoflurane in either group.We have demonstrated that sevoflurane significantly prolongs the QTc interval, and that the extent of the prolongation is significantly greater in chronically hyperglycemic patients than in normoglycemic patients. Although Tp-ec is not affected by sevoflurane, it should be noted that the simultaneous blockade of potassium channels would increase the risk of arrhythmias.

Sevoflurane prolonged the QTc interval and increased transmural dispersion of repolarization in a patient with long QT syndrome 3: a case report.

We report that sevoflurane not only caused marked QTc interval prolongation but also increased transmural dispersion of repolarization in a patient with long QT syndrome 3 (LQT3). A 16-year-old male with LQT3 underwent a shoulder operation. He experienced no episode of syncope or cardiac arrest, but his preoperative electrocardiography (ECG) showed marked QTc interval prolongation (631 ms) and Tp-e interval prolongation (126 ms). Anesthesia was induced with propofol and maintained with 2% sevoflurane and remifentanil. Although no lethal arrhythmias occurred in the perioperative period, not only the QTc interval but also Tp-e interval was further prolonged by sevoflurane. While sevoflurane has been recognized as a safe anesthetic in terms of QT interval prolongation, even in patients with long QT syndromes, we believe that sevoflurane might be avoided for poorly controlled LQT3 patients.

[Anesthetic Magagement of Emergency Thoracic Endovascular Aortic Repair Due to Massive Bleeding during Esophageal Cancer Operation].

A 69-year-old male patient with esophageal cancer underwent video assisted subtotal esophagectomy after neoadjuvant chemotherapy and radiation (50 Gy). Adhesion between esophagus and the aorta was so severe that the aortic arch was damaged and massive bleeding occurred during manipulation of the esophagus. However, as we had expected and prepared for the incident, we successfully managed it and emergency thoracic endovascular aortic repair could be performed by cardiac surgeons immediately. Preanesthetic careful consideration and preparation for surgical incidents are necessary for anesthesiologists.

Voluntary exercise induces neurogenesis in the hypothalamus and ependymal lining of the third ventricle.

In the adult hypothalamus and ependymal lining of the third ventricle, tanycytes function as multipotential progenitor cells that enable continuous neurogenesis, suggesting that tanycytes may be able to mediate the restoration of homeostatic function after stroke. Voluntary wheel running has been shown to alter neurochemistry and neuronal function and to increase neurogenesis in rodents. In the present study, we found that voluntary exercise improved the survival rate and energy balance of stroke-prone spontaneously hypertensive rats (SHRSP/Kpo). We also investigated the effect of exercise on the proliferation and differentiation of hypothalamic cells using immunoreactivity for tanycytes and neural markers. The proliferation of elongated cells, which may be the tanycytes, was enhanced in exercising SHRSP compared to sedentary rats before and after stroke. In addition, the proliferation of cells was correlated with the induction of fibroblast growth factor-2 in the subependymal cells of the third ventricle and in the cerebrospinal fluid. Some of the newborn cells of exercising SHRSP showed differentiation into mature neurons after stroke. Our results suggest that voluntary exercise correlates with hypothalamic neurogenesis, leading to recovery of homeostatic functions in the adult brain after stroke.

Preoperative Prevalence of J-Wave Syndrome Electrocardiographic Patterns and Their Association With Perioperative Cardiac Events.

OBJECTIVE: To evaluate the preoperative prevalence of each type of J-wave syndrome electrocardiographic pattern and its association with perioperative cardiac events. DESIGN: Retrospective study. SETTING: Single hospital university study. PARTICIPANTS: The study evaluated 930 patients who underwent gynecologic, abdominal, neurosurgical, orthopedic, and urologic surgeries. INTERVENTIONS: Preoperative standard 12-lead electrocardiogram (ECG) monitoring was performed, and each type of J-wave syndrome ECG pattern-types 1, 2, and 3 and Brugada syndrome-type-was evaluated. Incidence of perioperative cardiac events was investigated up to 1 year postoperatively using an electronic medical record system. MEASUREMENTS AND MAIN RESULTS: Data from 789 patients were included in the final study. Of these, 16 patients (2.0%) had J-wave syndrome: 7 patients (0.9%) had type-1 patterns; 5 patients (0.6%) had type-2 patterns; 2 patients (0.3%) had type-3 patterns; and 2 patients (0.3%) had Brugada syndrome-type ECG patterns. A J-point elevation≥0.2 mV, which is considered to be more dangerous, was found in only 2 patients with Brugada syndrome-type ECG patterns, both of whom suffered perioperative lethal arrhythmias. CONCLUSION: Patients with J-wave syndrome ECG patterns, even dangerous patterns, are not necessarily associated with a higher risk of perioperative cardiac events. However, Brugada syndrome type ECG patterns should be carefully monitored.